1-(6-Methoxy-2-naphthyl)ethyl hydroxymethylketone

ABSTRACT

1-Hydroxy-3-(2-naphthyl)ketones having three to five carbon atoms and derivatives optionally substituted in positions C-1, 4, 5, 7 and 8 and/or position C-6 of the naphthyl ring are antiinflammatory, analgesic and antipyretic agents.

United States Patent 1 Petracek Dec. 2, 1975 l-(6-METHOXY-2-NAPHTHYL)ETHYL HYDROXYMETHYLKETONE 56] References Cited [75] Inventor: Francis J. Petracek, Bloomington, OTHER PUBLICATIONS Minn Khan et al., J. Pharm. Pharmacol." Vol. 1. pp. [73] Assignee: Riker Laboratories, Inc., 230-234 (1949) Northndge Cahf' Primary Examiner-Norman Morgenstern [22] Filed May 3, 1972 Attorney, Agent, or Firm-Alexander, Sell, Steldt & 21 Appl. No.: 250,039 DeLaHum [57] ABSTRACT [52] Cl 260/590; 260/468 R; 260/468 G; l-Hydroxy-3-(2-naphthyl)ketones having three to five 260/468 K; 260/476 C; 260/479 R; 260/485 carbon atoms and denvatlves optlonally substltuted m F; 260/485 G; 260/485 H; 260/485 J;

posmons C-l. 4, 5, 7 and 8 and/or posmon C-6 of the 260/485 K; 260/488 CD; 424/299; 424/308; naphthyl ring are anti-inflammatory analgesic and an- 424/311; 424/312; 424/313; 424/331 tipyretic agents [51] Int. Cl. C07C 49/76; C07C 49/82 [58] Field of Search 260/590, 592 2 m N0 Drawings l-(fi-METHOXY-Z-NAPHTHYL )ETI-IYL HYDROXYMETI-IYLKETONE BACKGROUND OF THE INVENTION Derivatives of a-(2-naphthyl)acetic acid (South African Pat. No. 67/07,597) and B-(Z-naphthyDethanol (French Pat. No. 2,012,150) are known. However, these patents do not describe or suggest derivatives of l-hydroxyacetone. So far as is known to applicant, 3- (2-naphthyl)derivatives of l-hydroxyacetone have .not previously been reported.

This invention relates to novel naphthyl derivatives of l-hydroxyacetone and more particularly to 3-(2- naphthyl)derivatives of l-hydroxyacetone, optionally substituted additionally on the 3 position of the acetone moiety, and in which the naphthyl ring may be monosubstituted at the l, 4, 5, 6, 7, or 8 positions or disubstituted at the 6 and l, 4, 5, 7 or 8 positions. The invention also relates to methods for using said compounds and to processes for the preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are l-hydroxyacetone derivatives of the formula Formula I wherein one of R and R is hydrogen, the other is hydrogen, methyl, ethyl or difluoromethyl; or R and R taken together are methylene, halomethylene or ethylene; n is zero, one or two; and

I. when n is one a. when R is at C1, 4, 5, 7 or 8 it is alkyl, trifluoromethyl, fluoro, chloro, hydroxy, lower alkoxycarbonyl, lower alkoxy or lower alkylthio;

b. when R is at C6 it is alkyl, cycloalkyl, hydroxymethyl, lower alkoxymethyloxy, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, hydroxy, a conventional hydrolyzable ester, lower alkoxy or lower alkylthio, formyl, acetyl or aryl;

2. when n is two, one R is at C-6 and the other is at C-l, 4, 5, 7 or 8; and R is lower alkyl, fluoro, chloro, hydroxy, a conventional hydrolyzable ester, lower alkoxy or lower alkylthio; provided that when one of these R is hydroxy, alkoxy or alkylthio, the other is the identical group or alkyl, fluoro, chloro or a conventional hydrolyzable ester.

This invention also relates to methods for the preparation of compounds of Formula I' and methods for using the compounds as anti-inflammatories, analgesics and antipyretics.

The term halomethylene as used herein means monoor dihalomethylene groups wherein the halogen is fluorine or chlorine, such as fluoromethylene, chloromethylene, difluoromethylene and chlorofluoromethylene.

The term alkyl as used herein means straight or branched chain hydrocarbon groups of one to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiarybutyl, pentyl, hexyl and the like. By the term cycloalkyl is meant cyclic hydrocarbon groups of three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like. i

The term alkoxy means a straight or branched chain hydrocarbon ether group of six or less carbon atoms, including methoxy, ethoxy, 2-propoxy, propoxy, butoxy, 3-pentoxy and the like. Alkoxymethyloxy" groupings are methylether groups substituted with one alkoxy group; typical alkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy, isopropoxymethyloxy and the like. The term alkylthio means straight or branched chain hydrocarbon thioether groups of six or less carbon atoms, including methylthio, ethylthio, propylthio, 2-propylthio, 2-butylthio, pentylthio, 3-hexylthio and the like.

By the term aryl" is intended unsubstituted and psubstituted phenyl derivatives, such as phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-hydroxyphenyl, pmethoxyphenyl, p-ethylphenyl and the like.

The term conventional hydrolyzable ester," as used herein, denotes those hydrolyzable ester groups conventionally employed in the art, preferably those derived from hydrocarbon carboxylic acids, or their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain or cyclic structure, and preferably contain from one to twelve carbon atoms. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, 2-methyl propionate, butyrate, valerate, caproate, caprylate, benzoate, phenylacetate, diethylacetate, trimethylacetate, t-butylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, bicyclo[2.2.2]octyl carboxylate, hemisuccinate, hemiadipate, hemi-B,B-dimethylglutarate.

When one of R and R is hydrogen and the other is methyl, ethyl or difluoromethyl, thecompounds of Formula I can exist as pairs of enantiomorphs, one of which exhibits greater anti-inflammatory, analgesic, antipyretic and/or antipruritic activity than the other enantiomorph.

The compounds of Formula I that exist as enantiomorphs can be administered as mixtures of enantiomorphs or as resolved enantiomorphs.

The enantiomorphs are resolved by conventional means, such as by (a) selective biological degradation; or (b) by the preparation of derivatives of the compounds of Formula I, then the separation of the diastereoisomers by fractional crystallization and finally the regeneration of the optically resolved isomers of the compounds of Formula I from their respective resolved diastereoisomers.

Alternatively, and preferably, the resolved comv pounds of Formula I can be prepared from the corresponding resolved starting compounds used to prepare the compounds of Formula I. The resolved compounds 3 4 and their respective resolved starting compounds will When n is one, R is preferably substituted at C-5, 6 not necessarily have the same optical rotation although or 7, and most preferred is C-6. they will have the same absolute configuration. It is presently preferred that R is methyl, ethyl, me-

The compounds of the invention are useful in the thoxy, ethoxy, trifluoromethyl, fluoro, chloro and treatment of inflammation of the skin, respiratory tract, 5 methylthio, and most preferred is methoxy. musculoskeletal system, joints, internal organs and tis- The presently most preferred compounds of the insues. Accordingly, these compounds are useful in the vention are: l-hydroxy-3-(6-methoXy-2-naphthyl)- treatment of conditions characterized by inflammation, propanone and l-(6-methoxy-2-naphthyl)ethyl hysuch as contact dermatitis, allergic conditions, burns, droxymethyl ketone. rheumatism, contusion, arthritis, bone fracture, post- 10 The compounds of the invention are conveniently traumatic conditions and gout. In those cases in which prepared from the corresponding Z-naphthylacetic acid the above conditions include pain, pyrexia and pruriderivatives, or esters thereof, by a novel process which tus, coupled with the inflammation, the instant comcan be illustrated by the following reaction sequence:

0 Y o, o (1) ll ll ll Z COOR Z-C-Cl T Z-CCHN ZCCH OH pounds are useful for the relief of these conditions as wherein R is H or a lower alkyl radical and Z is well as the inflammation. For example, the instant com- 1 pounds are useful in the treatment of pain associated R with post-operative conditions, post-traumatic condii tions, post-partum conditions, dysmenorrhea, burns, i C

gout, contusions, neuralgia, neuritis, headaches and 3 l 2 R 0 R rheumatlc fever. As stated above, these compounds are n a L H exhibit antipyretic activity, accordingly, these compounds are useful in the treatment of pyrexia where re- Rea tion (1 uses any of the well-known methods for duction of a fever is indicated, for example, cases the preparation of acid chloride. Reaction with thionyl where high fever is associated with diseases such as chloride has been found to be a very convenient route rh m i r, bronchitis, p m yp r, for obtaining the acid chloride from the acid. Hodgkins disease and the like. The present compounds Reaction (2) with diazomethane is a well-known reare also useful in the treatment of pruritus where the action, discussed for example in Organic Reactions,

condition exists contemporaneously with inflamma- Vol. 1, pages 38 ff. It has been found to proceed roution, pain and/or high fever. Moreover, the compounds tinely in the class of compounds described by this inare useful for treating pruritus per se. vention. A non-reactive solvent such as diethyl ether is The preferred manner of oral administration proused. The diazoketone is a solid or liquid which may be vides the use of a convenient daily dosage regimen isolated but is generally not characterized. It is hydrowhich can be adjusted according to the degree of afflic- 40 l d as shown in step (3) under acidic conditions in a tiOIl- Generally, a daily dose of from gto 0 gsuitable solvent, for example dioxane and tetrahydrofuof the compound of Formula I per kilogram of body ran, with added water. Suitable acids for providing hyweight of the mammal is employed. Most conditions drogen ions for this reaction are organic or inorganic, respond to treatment comprising a dosage level of the e.g. sulfuric, perchloric or trifluoroacetic. Strong acids order of .5 mg. to 5 mg. per kilogram of body weight are preferred, generally in low concentrations. 7 per day. For such oral administration, a pharmaceuti- Compounds of the invention of Formula I wherein n cally acceptable, non-toxic composition is formed by is one or two are prepared by the reaction sequence dethe incorporation of any of the normally employed exscribed hereinabove and/or appropriate transformacipients. Suitable pharmaceutically acceptable carriers tions of one substituent to another on the structure of or excipients include starch, glucose, lactose, gelatin, Formula I by methods familiar to those skilled in the malt, flour, chalk, magnesium carbonate, magnesium art. Examples include reactions such as halogenation, stearate, glyceryl, monostearate, talc, dried skim milk, hydrolysis, ether cleavage and alkylation of hydroxy gylcerol, water, ethanol and the like. These composigroups. tions take the form of solutions, suspensions, tablets, When a resolved enantiomorph of Formula Z pills, capsules, powders, sustained release formulations COOR is employed in the reaction sequence described and the like. In addition, these compounds can be adhereinabove, the corresponding resolved enantioministered in conjunction with other medicinal agents morph of Formula I is obtained, depending upon the specific condition being treated. The starting material compounds of the Formula Z Preferred compounds of the invention are those COOR can be prepared byany one of several methods wherein one of R and R is hydrogen and the other is known to the art, and are generally known (see, for exhydrogen, methyl, ethyl or difluoromethyl, or R and R ample, in South African Pat. Nos. 67/07,597 and taken together are methylene or difluoromethylene. 68/04,?)78).

Most preferred are combinations wherein R and R are In the following examples the processes described are both hydrogen, or R is hydrogen and R is methyl. illustrative of procedures useful for obtaining the com- It is preferred that n is one or two, and most preferred pounds of this invention but are not intended to be limthat n is one. When n is two, one of R must be substiiting. Other processes are known and may be applied tuted at C-6, and it is preferred that the other R is at by those skilled in the art to obtain the compounds of position C-5 or 7. this invention.

EXAMPLE 1 6-Methoxy-2-naphthylacetic acid in dichloromethane is treated with excess thionyl chloride, and the mixture is heated to its reflux temperature and heated at reflux with stirring for several hours. Excess thionyl chloride is removed by twice adding benzene and evaporating under vacuum. Infrared spectral analysis of the product, 6-methoxy-Z-naphthylacetyl chloride, is conmatography on a silica gel plate and found to be good. Infrared spectral analysis of the product is consistent with the assigned structure.

All of the diazomethylketone is treated with excess 2N aqueous sulfuric acid in dioxane at 6065 C. for 0.5 hour. The mixture is diluted with water, then filtered to isolate the solid. Chromatography on a column of 75 percent silicic acid and 25 percent celite, folsistent with the assigned structure. It is used without 10 lowed by recrystallization from ethanol gives light yelfurther purification.

The acid chloride (10 g., 0.0426 mole) in diethyl ether l50 ml.) is gradually added to excess diazomethane in ether (250 ml.) at 0C. The mixture is stirred for 2 hours at 0 C., then evaporated under vacuum. The purity of the solid residue is checked by thin layer chro- TABLE I EX. No. Starting Material Final Product 0 0 2 6-methyl-2-naphthyl acetic acid [/OW O ,-CH CCH OH 0 ll 3 6-methyl-Z-naphthyl-a-methyl CHCCl-l OH acetic acid l 2 CH CH ll 7fluoro-2-naphthyl acetic acid F CH CCl-l OH Ychrh 2 Q 5 5,fi-dimethyl-Z-naphthyl-a- /CH-C-CH OH methyl acetic acid 1% ll CH 1" l 0 CH CH 6 7-chloro-2-naphthyl-a ,u- C1 C-C-CH OH methylene acetic acid ll 0 CH 7 7-methylthio-Z-naphthyl-a- CH S CH-C-CH OH ethyl acetic acid 3 ll 0 s CH 8 6-chloro-Z-naphthyl-a-methyl .I-CH-C-Cl-I OH acetic acid l H Cl 0 9 5-fluoro-Z-naphthyl-ot-ethyl Cl-l-C-Cl-l OH acetic acid H 2 low plates of l-hydroxy-3-(6-methoxy-2-naphthyl)- propanone, m.p. l26l30 C.

Analysis: Calculated for C H O C, 73.0; H, 6.13. Found: C, 73.4; H, 6.17.

In a similar manner, the following compounds of the invention are prepared from the corresponding acids.

TABLE' I (continued) Starting Material 8-tr'ifluoromethyl-Z-naphthylmom-methylene acetic acid 5-chloro-2-na phthyl acetic acid l-methoxy-Z-naphthyl acetic acid 5-methylthio-2-naphthyl-czmethyl acetic acid 6,7-dimethoxy-2-naphthy1-dmethyl acetic acid S-trifluoromethyl-Z-naphthyla,a-difluoromethylene acetic acid 5-methylthio-2-naphthyl acetic acid 6-niethylthio-2-naphthyl-d,d-

methylene acetic acid 7-trifluoromethyl-2-naphthyld-methyl acetic acid 7-methoxy-2-naphthyl-d-methyl acetic acid 6-difluoromethoxy-Z-naphthylm CH O Final Product CF 0 v v E-CCH OH CH CH CCH OH CH-CCH OH I g CH ca CCH OH O SCH3 TABLE I (continued) Starting Material Final Product 6-methoxy-2-naphthyl-a-difluoro- CH-CCH OH methyl acetic acid 1] o C11 0 CF H O ll G-chloro-Z-naphthyl-a-difluoro- CH-CCH OH methyl acetic acid W I C1 CF H 6-trifluoromethyl-2-naphthyl-a- CHCCH OH methyl acetic acid w I ll O CF CH 5-methy1-2-1iaphthjrl-cx-methyl CH-CCH 0H acetic acid w l I] 0 CH CH l-chloro-Z-naphthyl-d-thyl CH-CCH OH a aceticacid v m ll F CH 0 ll l-difluoromethylthio-E-naphthyl- CHC-CH OH a-methyL-acetic acid I 3 SCF H 8-hydroxy-2-naphthyl-a-ethy1 CH-CCH OH acetic acid l I] O 1 CH 6-fluoro-2-naphthyl-a-methyl acetic acid TABLE I (continued) EX. No. Starting Material Final Product 29 4-ethoxy-2-naphthyl-a G.- C-C-CH OH ethylene acetic acid ll (FR CH 00 11 0 ll 30 7-methyI-Z-naphthyl-u-methyl acetic acid EXAMPLE 31 d-2-(6-Methoxy-2-naphthyl)propionic acid (6.5 g., 0.043 mole) dissolved in dichloromethane is treated with excess thionyl chloride, and the mixture is refluxed for three hours with stirring. Benzene is added, and the excess thionyl chloride is .removed by twice azeotroping the solvents away in vacuo. Infrared spectral analysis of the product is consistent with the assigned structure. The product, d-2-(6-methoxy-2-naphthyl)propionyl chloride, is used without further purification.

The acid chloride obtained above is dissolved in diethyl ether and is added dropwise to a solution of diazomethane (in excess) in ether while stirring at 0 C. The mixture is stirred at 0 C. for 2 hours, the-n evaporated under vacuum. The solid residue is checked for purity by thin layer chromatography on a silica gel plate and found to be essentially all diazomethylketone.

CH W (FHCCH OH What is claimed is: l. The compound l-( 6-methoxy-2-naphthyl)ethyl hydroxymethylketonef 2. The compound d-l-(6-methoxy-2-naphthyl)ethyl hydroxymethylketone. 

1. THE COMPOUND 1-(6-METHOXY-2-NAPHTHYL)ETHYL HYDROXYMETHYLKETONE.
 2. The compound d-1-(6-methoxy-2-naphthyl)ethyl hydroxymethylketone. 